Eva Ihle, MD, PhD

Autism is demanding increased attention by professional and lay audiences; prevalence seems to be increasing. There are differing opinions about whether the increase is due to greater recognition and reporting, diagnostic expansion and substitution, or increasing acceptability. On the other hand, the increase may be a consequence of environmental toxins or infectious and immune vulnerability and epigenetics or perhaps a combination of social and environmental factors.

Clearly, autism has a large genetic component and multiple genes are involved in various combinations. Nevertheless, the prevalence of autism in the United States and in other countries has increased exponentially; this trend would not happen with a purely genetic disorder. Most autism researchers accept a theory of etiology that starts with a genetic neurodevelopmental vulnerability combined with an environmental stressor through such epigenetic processes as immune function.

Increasingly, researchers and clinicians refer to autism to describe a wide variety of phenotypes that start with genes and gene expression and range through a variety of metabolic functions to symptoms that cluster diagnostically but have a great deal of individuality. Symptoms can range from mild to severe and may be associated with mental retardation; GI and neurological involvement; and behavioral, emotional, cognitive, and whole body pathology.

Here we discuss diagnostic assessment and classification, co-occurring or comorbid psychiatric disorders and their differential diagnosis, the medical workup, and possible medical comorbidities. We also review a model for psychosocial treatment as well as psychopharmacological and alternative treatments. We conclude with a brief look at the future of research and treatment.

The term “autism (or autistic) spectrum disorder” (ASD) is likely to be replaced with “pervasive developmental disorder” in DSM-5. ASD is a collection of neurodevelopmentally based conditions of social and communicative impairments, each with varying severity and broadness of expression.

Autism was originally described by Leo Kanner in the early 1940s and termed “early infantile autism” of unknown etiology. By the 1960s, work on high concordance of autism in monozygotic twins and lower concordance in dizygotic twins and siblings led to the present-day understanding of ASD as a developmental and neurobiological condition with heterogeneous genetic and possible epigenetic triggers.

Diagnosis of ASD remains an empirical and behavioral procedure with no clear or single biological marker or assay. This has made reliable and valid diagnosis problematic: signs of ASD selected for inclusion in DSM have had fairly high diagnostic sensitivity but often poor specificity.

 Symptoms of ASD overlap with those of other neurodevelopmental disorders. Accurate differential diagnosis and diagnosis of comorbid conditions in ASD are therefore difficult.

The best practice for clinical assessment of ASD involves multiple methods of measuring multiple traits (

). Both parents and child contribute to data collection via interview and record review. The child is also observed directly or on video in the home, at school, and in the clinic under structured and unstructured conditions.

 The Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule (ADOS) are considered to be the gold standard in ASD diagnosis and are widely used in research.

Because a behavior can reflect different etiologies and symptoms can overlap, other disorders need to be carefully considered. Within the differential for ASD are anxiety disorders, attention-deficit/hyperactivity disorder (ADHD), and even prodromal schizophrenia or schizoid personality disorder.

When children are anxious, particularly when they have symptoms consistent with obsessive-compulsive disorder, they can manifest an inflexibility about routines (serving to bind their anxiety) and exhibit tics or behavioral compulsions that can be mistaken for stereotypies. Likewise, it can be difficult to delineate anxiety from the overwhelming biological basis for ASD in which learning deficits lead to anxious behavior.

Children with ADHD can seem socially impaired. But rather than having a deficit in theory of mind, the ability to understand another’s perspective through one’s own similar reasoning and experience, these children miss social cues (because they do not attend to them) or behave impulsively around peers, which can result in their being ostracised. The social withdrawal associated with thought disorders can be mistaken for the impairments in social interaction characteristic of ASD.

CHECKPOINTS 
? Signs of autism spectrum disorder (ASD) selected for inclusion in DSM have had fairly high sensitivity to the clinical diagnosis of autism, but they often show poor specificity.

? A diagnosis of autism can be made only if the child’s social interactions are not commensurate with his or her developmental level. 

? Psychiatric comorbidities, such as anxiety and attention-deficit/hyperactivity disorder, and medical comorbidities, such as epilepsy, sleep disorders, and Tourette syndrome, are frequent in ASD.

? ASD is heterogeneous in expression, and treatment plans must target ASD and comorbid disorders that may require integrated yet separate treatment.. 

? Psychopharmacological agents can help with symptoms of ASD, such as irritability, impulsivity, and anxiety; however, they do not seem to help directly with core symptoms of social reciprocity or communication, although they may do so indirectly through improved availability for treatment.

ASD can also be misdiagnosed in children who have a language disorder.

 Communication deficits can lead to social impairment, but these are secondary to limitations in reciprocal exchanges (and resultant frustration). In addition, the classification of receptive and expressive language disorders in DSM is nosologically different from American Speech-Language-Hearing Association standards.

While misdiagnosis can be a dilemma, overlooking a diagnosis can also be challenging. It is unclear why the diagnosis of intellectual disability is often missed, given that 50% to 70% of children with ASD have some level of intellectual disability.

Clinicians may be reluctant to make this diagnosis in children who are difficult to assess, or to discuss this diagnosis with parents. Alternatively, assessment of cognitive functioning may not be part of the clinical evaluation. Ideally, patients should undergo a battery of clinical assessments that includes a test of cognitive functioning. A diagnosis of autism can be made only if the child’s social interactions are not commensurate with his or her developmental level.

It is worth noting that disorders that can be mistaken for ASD can co-occur with ASD. The diagnosis of ASD does not exclude the possibility of a comorbid brain disorder. ADHD and anxiety disorders are frequently associated with ASD, with mood disorders occurring less frequently.

ASD is a heterogeneous set of disorders that is occasionally associated with (and secondary to) a particular neurological disease. In this situation, syndromic autism, there can be autistic features (ie, behaviors that appear to have their basis in a deficit in theory of mind) associated with, for example, tuberous sclerosis, fragile X syndrome, and agenesis of the corpus callosum.

Medical comorbidities, such as epilepsy, sleep disorders, and Tourette syndrome, are frequent in ASD. Their recognition and treatment form a core component of symptom management in affected individuals and highlight the importance of a multidisciplinary health care team.

Epilepsy occurs in up to one-third of individuals with ASD and suggests an imbalance of neural excitation and inhibition. Seizure onset has been noted to present during 2 peak periods: early childhood and adolescence.

 In addition, there is some suggestion of an increased risk of epilepsy in females and individuals with intellectual disability.

 Although there are no primary seizure types specifically associated with idiopathic ASD, specific neurogenetic disorders (eg, tuberous sclerosis complex, fragile X syndrome, chromosome 15q duplication syndrome, 

-related conditions) confer increased risk of ASD and epilepsy.

 There are also reports of higher rates of epileptiform electroencephalograms in children who do not have clinical seizures.

Sleep disorders affect up to two-thirds of children with ASD.

 Insomnias are predominant; however, parasomnias, breathing disorders, and movement disorders have also been reported.

Recent work in ASD genetics suggests a relationship between polymorphisms in the biological clock genes, 

 Although the effects of sleep disorders are difficult to separate from the effects of neurodevelopmental disability in general, insomnia is important to treat because it may exacerbate challenging behaviors, hyperactivity, cognitive deficits, headaches, and seizure frequency.

 For sleep difficulties related to disrupted circadian cycles, it may be helpful to limit daytime sleeping and caffeine intake and to ensure regular exercise. Exogenous treatment with melatonin may decrease time to sleep onset.

In patients with ASD, the prevalence of Tourette syndrome is increased (6.5%).

 Unifying theories posit a common genetic liability factor for ASD and tics; however, these theories have not been substantiated. Complex motor tics can be distinguished from common ASD stereotypies in that complex motor tics are involuntary, are quick and random, and tend to subside when an individual is engrossed in an activity. Behavioral and pharmacological interventions are only indicated when tics limit function and comfort.

Psychoeducational and behavioral treatments

Evidence-based ASD treatment must be intensive and individualized, with learning opportunities that are an integral part of educational and social interactions.

 Treatments for ASD begin with an understanding that the syndrome is heterogeneous in expression and that treatment plans must target ASD rather than comorbid disorders that may require integrated yet separate treatment. From the psychoeducational or behavioral treatment perspective, one heuristic for conceptualizing this clinical variability is to functionally translate DSM symptoms into autism-specific learning disabilities and autism-specific learning styles. This allows the clinician to think in terms of an autism treatment “toolbox” that can be used to assess a patient’s learning disabilities and learning styles and to choose specific intervention strategies to target them (

 Research standards support ASD treatments that are behavioral in meth-odology and developmental with respect to curriculum content.

Psychopharmacological agents can help with symptoms associated with ASD, such as irritability, impulsivity, anxiety, cognitive disorganization, aggression, difficulty in shifting attention from one area of interest to another, and distractible inattention. However, these medications do not seem to help directly with core symptoms of social reciprocity or communication, although improvement in the above-mentioned symptoms can help indirectly.

In 2006, the FDA approved risperidone to treat irritability in autism.

 On the basis of 2 studies, aripiprazole was approved for the same indication in November 2009.

 Other atypical antipsychotics have also been found to be effective in open-label trials. Except for ziprasidone, all are associated with weight gain, at least initially.

SSRIs have long been used to treat impulsivity, difficulty in shifting attention, anxiety, and repetitive behaviors on the basis of the finding of low serotonin levels in patients with ASD. However, a large, multisite, placebo-controlled trial of citalopram in ASD did not find significant differences on the Clinical Global Impression Improvement (CGI-I) scale or the Children’s Yale-Brown OC [obsessive-compulsive] Scale (CY-BOCS).

 Factors that may account for this could have been the 30% placebo response rate.

Other medications that might be judiciously considered in the treatment of ASD include stimulants, a2-adrenergic agonists, divalproex, and memantine.

 Alternative treatments under investigation include melatonin, ω-3 fatty acids, methyl B12, the casein-/gluten-free diet, digestive enzymes, hyperbaric oxygen therapy, and chelation. Most alternative treatments do not have published studies to guide treatment selection and for some, there is a question of safety.

The study of autism is progressing rapidly. Early identification and intervention is increasingly possible and effective.

 Further delineation of the gene-environment interaction theories of etiology are coming from large, collaborative studies. The number of treatment studies lags far behind that of studies of genetics and other etiologies, but the number is growing because of more sophisticated ideas about etiology and treatment targets.

Community organizations, school personnel, and treatment providers are gaining increasing skill at personalizing treatments for patients with autism, with significant improvements in outcome. The rising number of adults with ASD presents a considerable challenge for suitable housing, employment, and effective interventions. It is likely that facing these challenges and the new understandings that are being developed will benefit not only people with ASD but all people with neurodevelopmental disorders.

 Pardo CA, Eberhart CG. The neurobiology of autism. 

 Herbert MR. Contributions of the environment and environmentally vulnerable physiology to autism spectrum disorders. 

 Andrews G, Pine DS, Hobbs MJ, et al. Neurodevelopmental disorders: cluster 2 of the proposed meta-structure for DSM-V and ICD-11. 

Helping Children With Autism Learn: A Guide to Treatment Approaches for Parents and Professionals. 

New York: Oxford University Press; 2003.


 Siegel B, Ficcaglia M, Hayer C, et al. Treatment of pervasive developmental disorders. In: Weller E, McDermott J, Gabbard GO, eds.

 Gabbard’s Treatment of Psychiatric Disorders. 

4th ed. Washington, DC: American Psychiatric Association Press; 2007:79-92.


. Washington, DC: National Academy Press; 2001.


Articles

Autism is demanding increased attention by professional and lay audiences; prevalence seems to be increasing. There are differing opinions about whether the increase is due to greater recognition and reporting, diagnostic expansion and substitution, or increasing acceptability.

Author | Eva Ihle, MD, PhD

Articles

Update on Autism